Muscle dilemma: the great debate over myocyte expression in mRNA vaccination

“The DC is not bypassed; rather, its role shifts from a factory to a logistics hub"

The cellular basis of mRNA–lipid nanoparticle (LNP) vaccine immunogenicity has undergone significant revision, shifting from an early myocyte‑centric model toward recognition of professional antigen‑presenting cells (APCs) as the dominant site of mRNA translation. Emerging evidence supports a bifurcated mechanism: CD4+ T helper and antibody responses depend on endogenous APC translation, while CD8+ cytotoxic T cell priming relies on cross‑dressing, whereby dendritic cells acquire pre‑formed peptide–MHC class I complexes from the surface of non‑hematopoietic structural cells. This model resolves the apparent paradox of intact CD8+ responses following APC silencing, and positions the dendritic cell not as a translational factory but as a logistics hub for antigen acquisition. Variables including LNP formulation, mRNA dose, and dsRNA impurity levels are discussed as key modulators of pathway dominance, with implications for rational mRNA vaccine design.

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